SYNTHESIS: A well stirred suspension of 140 g anhydrous AlCl3 in 400 mL CH2Cl2 was treated with 102 g butyryl chloride. This mixture was added in small portions, over the course of 20 min, to a well-stirred solution of 110.4 g p-dimethoxybenzene in 300 mL CH2Cl2. After an additional 1 h stirring, the mixture was poured into 1 L H2O, and the two phases separated. The aqueous phase was extracted with 2×100 mL CH2Cl2, and the organic fractions pooled. These were washed with 4×125 mL 5% NaOH which removed both unreacted butyric acid as well as a small amount of 2-hydroxy-4-methoxybutyrophenone. Removal of the CH2Cl2 under vacuum gave 156.7 g of a residue that was distilled at 170–178 °C at the water pump. The isolated 2,5-dimethoxybutyrophenone was a pale yellow oil that weighed 146 g and was about 85% pure by GC analysis. The principal impurity was unreacted dimethoxybenzene. The identical preparation with CS2 as a solvent, rather than CH2Cl2 gave a somewhat smaller yield of product.
To 150 g mossy zinc there was added a solution of 3 g mercuric chloride in 60 mL H2O, and this was swirled periodically for 2 h. The H2O was drained off, and the amalgamated zinc added to a 1 L three-neck round-bottomed flask, treated with 80 mL concentrated HCl, and heated on the steam bath. A solution of 20.8 g of 2,5-dimethoxybutyrophenone in 45 mL EtOH containing 10 mL concentrated HCl was added in increments over a 4 h period. During this period an additional 140 mL of concentrated HCl was added periodically to the ketone solution. Heating was maintained for an additional 4 h. After cooling, the aqueous filtrate was extracted with 3×100 mL CH2Cl2 and these pooled extracts washed with 2×200 mL 5% NaOH to remove a small amount of phenolic impurity. After removal of the solvent under vacuum, the residual 16.1 g of clear oil was distilled over the 100–160 °C range (largely at 141–145 °C) at the water pump to give 10 g of 2,5-dimethoxy-n-butylbenzene as a white oil. This was about 90% pure by GC analysis, and was used without further purification in the next step.
A mixture of 98 mL POCl3 and 108 mL N-methylformanilide was allowed to incubate for 0.5 h. To this there was then added 47.3 g of 2,5-dimethoxy-n-butylbenzene and the mixture heated on the steam bath for 1.5 h. This mixture was poured into 1 L H2O and stirred overnight. The H2O was drained from the extremely gooey black crystals that were formed, and extracted with 2×100 mL portions of hexane. The black residue was diluted with these extracts and, on slow evaporation there was deposited 26.4 g of oily amber crystals. Filtering these through a medium porous funnel and sucking the oily phase away from the solids yielded 14.8 g of yellow crystals that could be recrystallized from 50 mL MeOH to give, after filtration and air drying to constant weight, 6.4 g of 2,5-dimethoxy-4-n-butylbenzaldehyde as pale yellow crystals with a mp of 47–48 °C. The recovery of all organic soluble things from the above process gave, after removal of the extraction solvents and making boiling hexane extractions of the residues, a second crop of aldehyde of equal weight and of identical mp. An analytical sample, from hexane, had the same mp. Anal. (C13H18O3) C,H.
A solution of 13.2 g 2,5-dimethoxy-4-n-butylbenzaldehyde in 50 mL acetic acid was treated with 4.0 g anhydrous ammonium acetate and 10 mL nitroethane. This mixture was heated on the steam bath for 4 h, then poured into a large quantity of H2O. This was extracted with 2×200 mL CH2Cl2, the extracts washed with H2O, and the solvent removed to give 19 g of a deep red oil. This was dissolved in 35 mL hot MeOH and slowly cooled, depositing yellow-orange crystals. These were removed by filtration, washed with cold MeOH, and air-dried to constant weight. Thus there was obtained 11.8 g of 1-(2,5-dimethoxy-4-n-butylphenyl)-2-nitropropene with a mp of 54–56 °C. Recrystallization of an analytical sample from MeOH tightened the mp to 55–56 °C. Anal. (C15H21NO4) C,H,N.
To a gently refluxing suspension of 8.5 g LAH in 300 mL anhydrous Et2O under a He atmosphere, there was added 11.0 g 1-(2,5-dimethoxy-4-n-butylphenyl)-2-nitropropene by allowing the condensing ether to drip into a Soxhlet thimble containing the nitrostyrene, thus effectively adding a warm saturated solution of it dropwise. Refluxing was maintained overnight, and the cooled reaction flask stirred for several additional days. The excess hydride was destroyed by the cautious addition of 600 mL H2O containing 55 g H2SO4. When the aqueous and Et2O layers were finally clear, they were separated, and 250 g of potassium sodium tartrate was dissolved in the aqueous fraction. Aqueous NaOH was then added until the pH was above 9, and this was then extracted with 3×200 mL CH2Cl2. Evaporation of the solvent produced 12 g of an amber oil that gelatinized to a waxy, amorphous mass. This was leached as thoroughly as possible with anhydrous Et2O which was clarified by filtration, then saturated with anhydrous HCl gas. After a few minutes delay, there commenced the separation of fine white crystals of 2,5-dimethoxy-4-n-butylamphetamine hydrochloride (DOBU). These weighed, after filtration, Et2O washing, and air drying to constant weight, 5.8 g. Recrystallization from boiling CH3CN (this is an unusually exothermic crystallization) yielded 5.4 g of a fluffy white product with mp 151–152 °C. Anal. (C15H26ClNO2) C,H,N.
DURATION: very long.
QUALITATIVE COMMENTS: (with 2.2 mg) “It was almost the fourth hour before I noticed something. Then I felt an increasing manic intoxication, winding up tighter and tighter. Sleep was impossible until some 18 hours after the start of the trial. There was some paresthesia, but no mydriasis. This might be a stimulant, but it is not a psychedelic, at least at this level. Go up slowly.”
(with 2.8 mg) “Nothing for over seven hours. Then there was what seemed to be an irritability and shortness of temper. Mentally I am completely clear, but no more alert than usual. There was no sleep that evening, and the next day there was a feeling of overall depression. Perhaps that was due to the lack of sleep, but there were no signs of residual sleepiness.”
EXTENSIONS AND COMMENTARY: It is not possible to give a dosage range for DOBU. There is no question but that whatever is occurring is slow of onset, and very long lived. In general, the effects resemble stimulation more that anything else.
A butyl group has four carbons, and they can be interconnected in four ways (as long as you don’t connect them in rings). If all four of them are in a straight chain, you have the so-called normal butyl (or n-butyl) group, and this is the exact arrangement that is found in the DOBU. The atoms can be numbered #1 through #4, going outwards from the point of attachment. The chain can, however, be only three carbons long, and the fourth or extra carbon attached on the #2 carbon atom; this is called the isobutyl (or i-butyl) group. Or the extra left-over carbon can be attached to the #1 carbon atom; this is called the secondary butyl (or sec-butyl or s-butyl) group. Or lastly, the atoms can be all scrunched up, with the chain only two carbons long, and the other two left-over methyl carbons attached to the #1 carbon atom. This isomer is called the tertiary butyl (or tert-butyl or t-butyl) group. In animal studies, and in preliminary human studies, the activity of these compounds drops as the butyl group gets more and more scrunched.
The isomer with the isobutyl group has been synthesized by the Friedel-Crafts reaction of isobutyryl chloride with p-dimethoxybenzene, followed by reduction of the ketone to an alcohol, dehydration to a dimethylstyrene, and final hydrogenation to a hydrocarbon. The formation of the benzaldehyde, reaction with nitroethane, and final lithium aluminum hydride reduction to 2,5-dimethoxy-4-(2-methylpropyl)amphetamine hydrochloride (
The last of the butyl isomers, the tert-butyl compound, was made from a much more obvious starting material. This is the commercially available tert-butyl hydroquinone. It was methylated in sodium hydroxide with methyl iodide, and then carried through the above sequence (benzaldehyde. mp 124 °C from cyclohexane, nitrostyrene, yellow crystals from methanol, mp 95–96.5 °C, and lithium aluminum hydride reduction) to give 2,5-dimethoxy-4-(1,1-dimethylethyl)amphetamine hydrochloride (
An effort was made to prepare a butyl analogue containing a ring, but it was never completed. This was the cyclopropylmethyl isomer, 2,5-dimethoxy-4-cyclopropylmethylamphetamine hydrochloride,
The 2-carbon phenethylamine homologues of these compounds could all, in principle be easily made by using nitromethane instead of nitroethane with the intermediary benzaldehydes. But, as of the present time, none of them have been made, so their pharmacology remains completely unknown.
13 May 2016 · · Isomer Design
About PiHKAL · info
This version of Book II of PiHKAL is based on the Erowid online version, originally transcribed by Simson Garfinkle and converted into HTML by Lamont Granquist. I drew also on “Tyrone Slothrop’s” (Unfinished) Review of PIHKAL to enumerate the many analogues mentioned in PiHKAL but not described at length. Many, many others have since been added.
I have tried here to expunge any artifacts introduced by the earlier transcriptions and restore the typographic niceties found in the printed edition. I’ve also made minor changes to some chemical names in line with current nomenclature practice. Typically the change is little more than expanding a prefix or setting it in italics. The history page has further details.
“At the present time, restrictive laws are in force in the United States and it is very difficult for researchers to abide by the regulations which govern efforts to obtain legal approval to do work with these compounds in human beings.“No one who is lacking legal authorization should attempt the synthesis of any of the compounds described in these files, with the intent to give them to man. To do so is to risk legal action which might lead to the tragic ruination of a life. It should also be noted that any person anywhere who experiments on himself, or on another human being, with any of the drugs described herein, without being familiar with that drug’s action and aware of the physical and/or mental disturbance or harm it might cause, is acting irresponsibly and immorally, whether or not he is doing so within the bounds of the law.”
The copyright for Book I of PiHKAL has been reserved in all forms and it may not be distributed. Book II of PiHKAL may be distributed for non-commercial reproduction provided that the introductory information, copyright notice, cautionary notice and ordering information remain attached.
PiHKAL is the extraordinary record of the authors’ years exploring the chemistry and transformational power of phenethylamines. This book belongs in the library of anyone seeking a rational, enlightened and candid perspective on psychedelic drugs.
Though Sasha and Ann have put Book II of PiHKAL in the public domain, available to anyone, I strongly encourage you to buy a copy. We owe them — and there’s still nothing quite like holding a real book in your hands.
PiHKAL (ISBN 0-9630096-0-5) is available for US$24.50 (plus $10 domestic first-class shipping) from Transform Press.Transform Press,
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